The era of individualized genetic medicine is fast approaching. Remarkable technical advances have brought the search for rare pathogenic variants to the fore in studies of complex disorders, redefining the focus of 'risk variant'from the population based cohort to the individual patient. Such studies have identified structural variations and complex genomic rearrangements as key variants associated with autism and other neuropsychiatric phenotypes, suggesting neurological pathways may be particularly sensitive to fusion genes and dosage effects. Yet current methods to map such variants remain imprecise, unable to detect balanced rearrangements and inversions, potentially bypassing a highly informative patient subgroup. This fellowship intends to address this significant deficit in our understanding of the impact of genomic rearrangements on neurodevelopmental abnormalities. The studies proposed herein will use "next- generation" sequencing to identify genes disrupted by apparently balanced rearrangements. They will build upon innovations in cancer genetics, customizing them for analysis of abnormal germline karyotypes. A massively parallel paired-end strategy of sequencing jumping clones will be used to first map precise breakpoints in autism spectrum disorder (ASD) patients with known genomic rearrangements (Aim I), then conduct comprehensive molecular analysis of disrupted gene(s) and pathways (Aim 11). Relying on methodological optimization, Aim 111 will seek to screen a large independent cohort of patients diagnosed with ASD and other disorders to identify consistent rearrangements and/or novel rare mutations. These studies will thus sequentially build in both scope and sophistication to address an important and understudied patient cohort. Collectively, they could yield important progress in focusing genetic risk to the individual genome, potentially delivering genotype-based classification as a pragmatic diagnostic tool in pediatric clinical practice. Public Health Relevance: The heritability of autism and related neurodevelopmental disorders is high but contributing genetic risk factors remain uncertain. The true incidence of genomic rearrangements in these patient groups could be substantially underestimated due to technological limitations. Novel methods for rapid screening are therefore needed. These studies could facilitate new diagnostic classifications that account for individual genomic events, explain a meaningful proportion of disease variance that is currently unknown, and help elucidate causative pathways.